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Central Sleep Apnea

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Abstract

Neurophysiologically, central apnea is due to a temporary failure in the pontomedullary pacemaker generating breathing rhythm. As a polysomnographic finding, central apneas occur in many pathophysiological conditions. Depending on the cause or mechanism, central apneas may not be clinically significant, for example, those that occur normally at sleep onset. In contrast, central apneas occur in a number of disorders and result in pathophysiological consequences. Central apneas occur commonly in high‐altitude sojourn, disrupt sleep, and cause desaturation. Central sleep apnea also occurs in number of disorders across all age groups and both genders. Common causes of central sleep apnea in adults are congestive heart failure and chronic use of opioids to treat pain. Under such circumstances, diagnosis and treatment of central sleep apnea may improve quality of life, morbidity, and perhaps mortality. The mechanisms of central sleep apnea have been best studied in congestive heart failure and hypoxic conditions when there is increased CO2 sensitivity below eupnea resulting in lowering eupneic PCO2 below apneic threshold causing cessation of breathing until the PCO2 rises above the apneic threshold when breathing resumes. In many other disorders, the mechanism of central sleep apnea (CSA) remains to be investigated. © 2013 American Physiological Society. Compr Physiol 3:141‐163, 2013.

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Figure 1. Figure 1.

A 30‐s epoch of a polysomnogram of a patient with systolic heart failure showing a central apnea in N2 nonrapid eye movement sleep. Note the gradual decrease in PES, ABD, RC, and RC + ABD followed by a gradual symmetric increase in these tracings out of central apnea sandwiched between the thoracoabdominal excursions. During central apnea, PES remains constant indicating lack of any activity of thoracic pump muscles. Desaturation occurs later in the epoch because of the long circulation time. Note the arousal at the peak of hyperventilation. Also, note relatively large excursions in the PES at the time of hyperventilation. The latter occurs because of the stiff lung. From top to bottom: EOG, electrooculogram; EEG, electroencephalogram; EKG, electrocardiogram; CO2, naso‐oral CO2 tracing representing airflow; RC, ribcage; ABD, abdominal wall movement measured by respitrace belts; RC + ABD, respitrace sum tracing; PES, esophageal pressure; SaO2, arterial oxyhemoglobin saturation.

Figure 2. Figure 2.

Loop gain (LG) depicts the ratio of ventilatory response to disturbance ratio. (A) Example of a LG of 0.72. The ventilatory control system is disturbed with a transient reduction in ventilation (a). This produces a response (b) in the opposite direction that is 72% as large as the disturbance. The next response (c) will also be 72% as large as (b), etc. Thus, a LG of 0.72 produces transient fluctuations in ventilation, but ventilation eventually returns to baseline. (B) A LG ≥ 1 will produce a response that is equal or greater in magnitude to the disturbance. Ventilation, therefore, oscillates without returning to baseline. The system in B is highly unstable. The closer LG is to zero, the smaller the fluctuations in ventilation, and thus the more stable the system (Fig. below, illustrates how the magnitude of ventilatory overshoots and undershoots, that is, stability, are determined by two key components of loop gain, namely, controller and plant gains). Reproduced, with permission, from Wellman et al. ().

Figure 3. Figure 3.

Diagrammatic representation of the steady‐state relationship between alveolar ventilation and alveolar PCO2 (PaCO2) at a fixed resting CO2 production (of 250 mL/min); PaCO2 = . The schematic figure shows how changing plant gain (A, top) or controller gain (B, bottom) will influence the “CO2 reserve” or Δ PaCO2 between eupnea and apnea. (A) Changing the background drive to breathe without changing the slope of the versus Δ PaCO2 relationship above or below eupnea. For example, background hyperventilation (via metabolic acidosis or specific CB stimulation with Almitrine) raises and lowers PACO2 along the isometabolic hyperbola. This means that a greater transient increase in V and reduction in PACO2 is required to reach the apneic threshold than it would be under control, normocapnic conditions. The reverse is true for conditions that reduce the background drive to breathe and cause hypoventilation [for example, metabolic alkalosis ()]. (B) At any given level of background PACO2, changing the slope (or responsiveness) of the relationship below eupnea would alter the CO2 reserve or the amount of reduction in PACO2 required to cause apnea. Changing the slope of the ventilatory response to CO2 above eupnea would alter the susceptibility for transient ventilatory overshoots. Often both plant and controller gains may change together, that is, note the reduced plant gains and increased controller gain, with hypoxia or with CHF patients. The increased control gain dominates and the net effect is a decreased CO2 reserve and instability. See text for a discussion of conditions that change controller and/or plant gain, and therefore, the susceptibility to transient ventilatory overshoots to apnea and ventilatory instability in sleep. Detailed discussions of the components of loop gain may be found in references (; ).

Figure 4. Figure 4.

Representative tracings of SaO2 and tidal volume taken from one subject during administration of CO2 in hypoxia nonrapid eye movement sleep. CO2 is added at arrow during the initial night at 4300 m simulated altitude. Nitrogen was also added to the inspirate (along with CO2) so that the average SaO2 was unchanged. Note that periodic breathing was completely eliminated with an average increase of about 1 mmHg in PaCO2. Similarly, the periodic breathing in CHF patients is eliminated via the use of added FICO2 via rebreathing (see text). Reproduced, with permission, from Berssenbrugge et al. ().

Figure 5. Figure 5.

A 10‐min epoch of periodic breathing with central sleep apnea in a patient with systolic heart failure, a pattern referred to as Hunter‐Cheyne‐Stokes breathing. Note the gradual reduction in various respiratory channels followed by central apnea and then a gradual rise in thoracoabdominal excursions following the apneas. Also, note that the central apneas are virtually of the same duration. This is in contrast to opioid‐induced central apneas depicted in Figure .

Figure 6. Figure 6.

Prevalence of sleep apnea in systolic heart failure in 1250 consecutive patients gathered from combining studies from different countries. AHI, apnea hypopnea index; CSA, central sleep apnea; OSA, obstructive sleep apnea. Adapted, with permission, from Javaheri et al. ().

Figure 7. Figure 7.

A 10‐min epoch of a polysomnogram of a patient on chronic opioids. The tracings are the same as in Figure . Note the differences in the pattern of breathing between this patient and the patient with heart failure in Figure . The central apneas are of different duration. There are obstructive hypopneas and apneas also present. Note that out of apnea, there are at times very large breaths.

Figure 8. Figure 8.

Modulation of breathing patterns by the mu‐opioid agonist [D‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin (DAMGO) at the pre‐Botzinger complex across sleep‐wake states in adult rats during wakefulness and sleep. Please note the depression in respiratory rate by application of DAMGO which is reversed by naloxone, a mu‐receptor antagonist. These changes are particularly pronounced in nonrapid eye movement (NREM) sleep. There is a significant reduction in respiratory rate as noted by diaphragmatic activity both during wakefulness and NREM sleep. The reduction in respiratory rate is primarily due to prolongation of the expiratory time. EEG, electroencephalogram; DIA, diaphragm. Adapted, with permission, from Montandon et al. ().

Figure 9. Figure 9.

Modulation of the genioglossus muscle activity by application of fentanyl, mu‐opioid receptor agonist at the hypoglossal motor pool in adult rats. Note the progressive increase of genioglossus moving time average (MTA) that parallels increasing concentration of fentanyl at the hypoglossal motor neuron pool. There is a similar reduction in genioglossal electromyogram (EMG) without a significant change in diaphragmatic MTA. Intravenous administration of naloxone, a mu‐opioid antagonist reverses changes in genioglossus muscle EMG and MTA. Adapted, with permission, from Hajiha et al. ().



Figure 1.

A 30‐s epoch of a polysomnogram of a patient with systolic heart failure showing a central apnea in N2 nonrapid eye movement sleep. Note the gradual decrease in PES, ABD, RC, and RC + ABD followed by a gradual symmetric increase in these tracings out of central apnea sandwiched between the thoracoabdominal excursions. During central apnea, PES remains constant indicating lack of any activity of thoracic pump muscles. Desaturation occurs later in the epoch because of the long circulation time. Note the arousal at the peak of hyperventilation. Also, note relatively large excursions in the PES at the time of hyperventilation. The latter occurs because of the stiff lung. From top to bottom: EOG, electrooculogram; EEG, electroencephalogram; EKG, electrocardiogram; CO2, naso‐oral CO2 tracing representing airflow; RC, ribcage; ABD, abdominal wall movement measured by respitrace belts; RC + ABD, respitrace sum tracing; PES, esophageal pressure; SaO2, arterial oxyhemoglobin saturation.



Figure 2.

Loop gain (LG) depicts the ratio of ventilatory response to disturbance ratio. (A) Example of a LG of 0.72. The ventilatory control system is disturbed with a transient reduction in ventilation (a). This produces a response (b) in the opposite direction that is 72% as large as the disturbance. The next response (c) will also be 72% as large as (b), etc. Thus, a LG of 0.72 produces transient fluctuations in ventilation, but ventilation eventually returns to baseline. (B) A LG ≥ 1 will produce a response that is equal or greater in magnitude to the disturbance. Ventilation, therefore, oscillates without returning to baseline. The system in B is highly unstable. The closer LG is to zero, the smaller the fluctuations in ventilation, and thus the more stable the system (Fig. below, illustrates how the magnitude of ventilatory overshoots and undershoots, that is, stability, are determined by two key components of loop gain, namely, controller and plant gains). Reproduced, with permission, from Wellman et al. ().



Figure 3.

Diagrammatic representation of the steady‐state relationship between alveolar ventilation and alveolar PCO2 (PaCO2) at a fixed resting CO2 production (of 250 mL/min); PaCO2 = . The schematic figure shows how changing plant gain (A, top) or controller gain (B, bottom) will influence the “CO2 reserve” or Δ PaCO2 between eupnea and apnea. (A) Changing the background drive to breathe without changing the slope of the versus Δ PaCO2 relationship above or below eupnea. For example, background hyperventilation (via metabolic acidosis or specific CB stimulation with Almitrine) raises and lowers PACO2 along the isometabolic hyperbola. This means that a greater transient increase in V and reduction in PACO2 is required to reach the apneic threshold than it would be under control, normocapnic conditions. The reverse is true for conditions that reduce the background drive to breathe and cause hypoventilation [for example, metabolic alkalosis ()]. (B) At any given level of background PACO2, changing the slope (or responsiveness) of the relationship below eupnea would alter the CO2 reserve or the amount of reduction in PACO2 required to cause apnea. Changing the slope of the ventilatory response to CO2 above eupnea would alter the susceptibility for transient ventilatory overshoots. Often both plant and controller gains may change together, that is, note the reduced plant gains and increased controller gain, with hypoxia or with CHF patients. The increased control gain dominates and the net effect is a decreased CO2 reserve and instability. See text for a discussion of conditions that change controller and/or plant gain, and therefore, the susceptibility to transient ventilatory overshoots to apnea and ventilatory instability in sleep. Detailed discussions of the components of loop gain may be found in references (; ).



Figure 4.

Representative tracings of SaO2 and tidal volume taken from one subject during administration of CO2 in hypoxia nonrapid eye movement sleep. CO2 is added at arrow during the initial night at 4300 m simulated altitude. Nitrogen was also added to the inspirate (along with CO2) so that the average SaO2 was unchanged. Note that periodic breathing was completely eliminated with an average increase of about 1 mmHg in PaCO2. Similarly, the periodic breathing in CHF patients is eliminated via the use of added FICO2 via rebreathing (see text). Reproduced, with permission, from Berssenbrugge et al. ().



Figure 5.

A 10‐min epoch of periodic breathing with central sleep apnea in a patient with systolic heart failure, a pattern referred to as Hunter‐Cheyne‐Stokes breathing. Note the gradual reduction in various respiratory channels followed by central apnea and then a gradual rise in thoracoabdominal excursions following the apneas. Also, note that the central apneas are virtually of the same duration. This is in contrast to opioid‐induced central apneas depicted in Figure .



Figure 6.

Prevalence of sleep apnea in systolic heart failure in 1250 consecutive patients gathered from combining studies from different countries. AHI, apnea hypopnea index; CSA, central sleep apnea; OSA, obstructive sleep apnea. Adapted, with permission, from Javaheri et al. ().



Figure 7.

A 10‐min epoch of a polysomnogram of a patient on chronic opioids. The tracings are the same as in Figure . Note the differences in the pattern of breathing between this patient and the patient with heart failure in Figure . The central apneas are of different duration. There are obstructive hypopneas and apneas also present. Note that out of apnea, there are at times very large breaths.



Figure 8.

Modulation of breathing patterns by the mu‐opioid agonist [D‐Ala2, N‐MePhe4, Gly‐ol]‐enkephalin (DAMGO) at the pre‐Botzinger complex across sleep‐wake states in adult rats during wakefulness and sleep. Please note the depression in respiratory rate by application of DAMGO which is reversed by naloxone, a mu‐receptor antagonist. These changes are particularly pronounced in nonrapid eye movement (NREM) sleep. There is a significant reduction in respiratory rate as noted by diaphragmatic activity both during wakefulness and NREM sleep. The reduction in respiratory rate is primarily due to prolongation of the expiratory time. EEG, electroencephalogram; DIA, diaphragm. Adapted, with permission, from Montandon et al. ().



Figure 9.

Modulation of the genioglossus muscle activity by application of fentanyl, mu‐opioid receptor agonist at the hypoglossal motor pool in adult rats. Note the progressive increase of genioglossus moving time average (MTA) that parallels increasing concentration of fentanyl at the hypoglossal motor neuron pool. There is a similar reduction in genioglossal electromyogram (EMG) without a significant change in diaphragmatic MTA. Intravenous administration of naloxone, a mu‐opioid antagonist reverses changes in genioglossus muscle EMG and MTA. Adapted, with permission, from Hajiha et al. ().

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S. Javaheri, J.A. Dempsey. Central Sleep Apnea. Compr Physiol 2013, 3: 141-163. doi: 10.1002/cphy.c110057